Cesium carbonate → 2-Bromo-4-fluoro-6-(10-fluoro-1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzyl Acetate

HRID 1026478Notes

Reaction equation

HRID 1026478 reaction equation
[C:1]([O:4][CH2:5][C:6]1[C:11]([Br:12])=[CH:10][C:9]([F:13])=[CH:8][C:7]=1Br)(=[O:3])[CH3:2].[F:15][C:16]1[C:24]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=2[N:18]2[CH2:25][CH2:26][NH:27][C:28](=[O:29])[C:17]=12.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:27]2[CH2:26][CH2:25][N:18]3[C:19]4[CH2:20][CH2:21][CH2:22][CH2:23][C:24]=4[C:16]([F:15])=[C:17]3[C:28]2=[O:29])=[CH:8][C:9]([F:13])=[CH:10][C:11]=1[Br:12])(=[O:3])[CH3:2]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 670165932,6-Dibromo-4-fluorobenzyl acetateHCID 8676245710-Fluoro-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one

Product 1

HCID 866837502-Bromo-4-fluoro-6-(10-fluoro-1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzyl AcetateYield 58.1%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 1,4-dioxane (60 mL), 2,6-dibromo-4-fluorobenzyl acetate 101C (2.34 g, 7.2 mmol), 119b (500 mg, 2.4 mmol), and cesium carbonate (1.6 g, 4.8 mmol). After bubbling nitrogen through the resulting mixture for 30 minutes, Xantphos (140 mg, 0.24 mmol) and tris(dibenzylideneacetone)dipalladium(0) (220 mg, 0.24 mmol) were added and the reaction mixture was heated at 100° C. for 12 h. After this time the reaction was cooled to room temperature and filtered. The filtrate was partitioned between ethyl acetate (40 mL) and water (40 mL). The aqueous layer was separated and extracted with ethyl acetate (3×70 mL). The combined organic layer was washed with brine (30 mL) and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column eluting with 3:1 petroleum ether/ethyl acetate to afford 119c (632 mg, 58%) as a yellow solid. MS: [M+H]+ 453.2

Workup

  1. customA 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer
  2. temperaturereflux condenser
  3. customAfter bubbling nitrogen through the resulting mixture for 30 minutes
  4. temperatureAfter this time the reaction was cooled to room temperature
  5. filtrationfiltered
  6. customThe filtrate was partitioned between ethyl acetate (40 mL) and water (40 mL)
  7. customThe aqueous layer was separated
  8. extractionextracted with ethyl acetate (3×70 mL)
  9. washThe combined organic layer was washed with brine (30 mL)
  10. dry with materialdried over sodium sulfate
  11. customThe drying agent was removed by filtration
  12. concentrationthe filtrate was concentrated under reduced pressure
  13. customThe residue was purified by silica-gel column
  14. washeluting with 3:1 petroleum ether/ethyl acetate

Sources & evidence

ORD record
ord-87577e9173444d0f9f0abe20e029c583
Source dataset
uspto-grants-2014_05
Patent number
US08729072B2

Reaction notes

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